Saturday, August 21, 2010

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For better or worse, we are constantly changing the world around us. The animals closest to us often experience this process the most. For thousands of years, people have domesticated animals for food, clothing, various other products, and companionship.

With the advent of genetic modification (GM), we have become able to mold animals much more quickly and directly than ever before. While this technology has already proven to be quite useful and promises to be even more advantageous, it must be used with much caution and prudence.

Since their creation over three decades ago, genetically modified animals have quickly found their way into many different fields. From their inception in research laboratories, where they continue to be used to this day to help solve basic biology questions, the farm industry seized hold of GM animals and by the early 1990s many fast-growing, disease-resistant livestock animals had already been created. At the same time, the pharmaceutical industry realized the potential of GM technology and generated livestock that could produce all kinds of drugs, quickly and in large quantities, in farm animals’ milk. Even the pet industry reached out for a slice of the GM pie, creating the “GloFish,” zebrafish that fluoresce bright colors. Truly, GM applications to animals have come a long way in a very short time.

GM Animals to Study Human Diseases: The first animal to be genetically modified was the mouse, not surprising given its century-long relationship with scientists. Because mice are similar to humans in many ways, take up relatively little space, and reproduce quickly and in great numbers, they are ideal models for us to study when trying to better understand our own biology (as was explored previously by Biology Bytes).

It was over 30 years ago, in 1975, that Rudolf Jaenisch, Hung Fan, and Byron Croker (at The Salk Institute for Biological Sciences in San Diego and the Scripps Clinic in La Jolla) showed that a virus could be used to deliver genes to a mouse. Specifically, they harvested mouse embryos, infected them with the natural, unmodified Moloney murine leukemia virus, implanted these embryos into a surrogate mouse mother, and found the baby mice had DNA in their tissues from the virus. (As an interesting aside, it’s been found that up to eight percent of the human genome has DNA from viruses; a virus integrating its genes into other genomes is not a new phenomenon.)

Researchers quickly realized that they could use viruses to deliver all sorts of different genes into animals. By the early 1980s, several mouse lines (lineages descended from the original modified parents) had been made that contained “foreign” genes in their genomes and could pass these genes on to their offspring. (Such animals are also commonly called “transgenic.”) While this was originally done using viruses, researchers found they could also inject DNA right into a fertilized mouse egg, although this approach is often less effective.

So what is the point of altering the genetics of mice? As mentioned above, mice are great models for studying human biology. Through genetic modification, mice have been made, for example, with development abnormalities that mimic ones seen in humans to help us better understand how the abnormalities are caused and, consequently, how they can be treated and/or prevented. Today, mouse models of countless human diseases and conditions have been created, and more are made in laboratories all the time, assisted by the completion of the sequencing of the mouse genome in 2002.

Many other animals have also had their genetics altered to study different aspects of human biology. Researchers studying fruit flies (specifically Drosophila melanogaster) quickly took advantage of burgeoning GM technology. Fruit flies were the first widely used model organism. By the early 1980s researchers were adding foreign genes to fruit fly genomes to better understand development, which was already well characterized in them. A wide range of other animals have been genetically modified that may help us better understand ourselves. Most recently, in 2009, scientists were able to introduce a gene into a primate for the first time (in marmosets); these monkeys and their offspring glow green under UV light.

Genetically Modified Farm Animals: With GM technology becoming well understood in mice, the livestock industry recognized this technology’s great potential. By the early 1990s, researchers had made the first transgenic pigs, sheep, dairy cows, and fish, signaling the beginning of a GM farm animal revolution.

The genes most frequently inserted are used to make the animals produce more growth hormones, which consequently make them grow faster and larger, and often produce higher quality meat or milk. Farm animals have also been genetically modified to be more disease resistant; the first pigs resistant to viral infections were created in 1992, and in 2005 cows that were resistant to bacterial infection related to mastitis (inflammation of the breast tissue, a common ailment of dairy cows) were made. Today, disease resistances have also been genetically added to poultry and fish, among others.

The fish industry is often overlooked when thinking of “farm” animals, but as an industry that processes 500 million pounds of meat annually, it has reason to explore GM technology. In 1992, Choy Hew and colleagues (at the Hospital for Sick Children and Departments of Clinical Biochemistry and Biochemistry at the University of Toronto) created GM Atlantic salmon that, by one year old, were an average of twice to six times as large as their non-GM relatives, with some fish as much as 13 times larger. Again, this was accomplished by injecting the gene of a growth hormone into the fish eggs.

Several other farm fish have been genetically modified, including trout (which also belongs to the salmon family), carp, and tilapia, usually to improve their growth rates. For example, in 2001, transgenic tilapia were created that could more efficiently digest dry protein diets, resulting in fish that were two times to five times larger than the non-transgenic tilapia. Such fast-growing GM animals are often referred to as “feeding machines.”

However, already researchers have discovered “natural” limits to the GM approach of increasing farm animal growth. Interestingly, in 2001, when a strain of domesticated, commercial, fast-growing rainbow-trout had growth hormone genes inserted into their genomes, their growth did not significantly increase, although their slower-growing, wild relatives had a 17-fold weight increase with the addition of the gene. The domesticated trout may have already reached a kind of growth ceiling due to decades of selection by fish farmers. Other studies have suggested that although GM fish may grow significantly faster, they may be more susceptible to disease and have reduced swimming abilities. Clearly there are currently limits to what GM additions can accomplish for the meat industries.

Some environmentally-conscious researchers have created animals that produce less waste. At the end of the 1990s, researchers at the University of Guelph in Ontario, Canada, created the “Enviropig,” a pig that produces less phosphorous in its manure. Why is this good for the environment? Because the manure of pigs on commercial diets contains high amounts of phosphorous which can leach into the nearby watershed, contaminating ponds, lakes, and rivers, and resulting in algal growth, fish kills, and undrinkable water. The Enviropig produces a protein (introduced by scientists) that allows it to absorb more of the phosphorous in its diet, so 30 to 70 percent less phosphorous comes out the other end. In February 2010, the promising Enviropigs received approval by the Canadian government to live outside of research facilities, in facilities separated from other animals.

The Perpetual Fight Against Pests: Researchers have furthermore used GM technology to defend crops from pests by targeting the pests themselves. The pink bollworm (Pectinophora gossypiella) is a very resilient pest of cotton farmers (it’s even resistant to cotton genetically modified with pesticides). Consequently, researchers created genetically modified, sterile pink bollworms in attempts to keep the pest’s numbers down; sterile males released over the crops mate with females, but the eggs do not become fertilized, causing a massive population drop.

Researchers have even altered bacteria in the guts of insects. The bacteria (Xylella fastidiosa), carried in the guts of a leafhopper insect, is responsible for Pierce’s disease in grapevines. Instead of attacking the guilty bacteria directly, researchers tried to improve its competitor, another bacteria (Alcaligenes) that also resides in the leafhopper’s guts. While it’s hoped that the GM bacteria will displace the culpable bacteria in the guts, field trials are needed to confirm this. However, because any grapevines that the studies are conducted on will have to be destroyed afterwards (GM studies require very stringent safety protocols until they are confirmed to be safe), researchers are having a hard time finding an area in which to test these GM leafhoppers.

The battle against pests is a tough one: Every 60 days a new disease or pest finds its way into California. GM technologies are a valuable addition to the suite of tools used to fight them.

Got Anti-Thrombin?: The use of animals to produce pharmaceutical products is one of the areas of GM technology that is being most heavily investigated today. Livestock have been genetically modified since the 1990s to produce a wide range of pharmaceutical proteins or biomaterials in their milk, including: coagulation factors, anti-clotting agents, anti-thrombin, calcitonin, altered milk proteins, tissue plasminogen activator, vaccines, and even spider silk, among many others (including some that are also produced in bacteria).

If some of these proteins were already made in bacteria, what’s the advantage to making them in animals? One big reason is that some proteins cannot be properly created in bacteria and need a mammalian system to be produced correctly in an active form. Additionally, livestock can rapidly make large amounts of a desired protein: In one liter of milk, two grams of the introduced protein can be produced. Dairy goats were created in 1991 that could milk out anti-thrombin III (important for treating thrombosis and pulmonary embolism); the estimate was that 75 goats could produce 75 kilograms in one year, meeting the world demand with a small herd. However, there have occasionally been some problems in such GM livestock animals, ranging from sterility, to premature cessation of lactation, to other rare undesired side-effects.

In addition to farm animals, mice have been used as “drug factories.” Mice were created in 2002 that produced desired proteins, including erythropoietin, in their urine. However, while this means the protein can be harvested throughout the lifetime of the animal, it is probably not as efficient as milking livestock.

Hurdles: As with any developing technology, there are still many hurdles to overcome in the field of genetically modified animals. When genes are added to livestock to make them grow more efficiently or produce pharmaceutical drugs in their milk, there can be undesirable side-effects that are very difficult to predict.

Additionally, although cows and goats can produce large quantities of pharmaceutical drugs in their milk, it can still be difficult to purify the drugs out of the milk, separating them from the normal milk proteins.

There are also many concerns over how GM animals may affect their environment, which can only begin to be predicted through extensive laboratory work where as many conditions as possible are tested. While GM technology holds immense promise, foresight and careful analysis is clearly required to properly fulfill it.

Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at science@independent.com.

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